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Nature of fetal adaptation to the uterine environment: a problem of sensory deprivation
Nature of fetal adaptation to the uterine environment: S.
R.
Chicago,
M.
a problem of sensory deprivation
REYNOLDS,
PH.D.,
D.Sc.
Illinois
0 B S T E T R I c I A N s are concerned with fetal cardiovascular physiology whenever they listen to a fetal heart. The problem is to distinguish between “normal” and “distress” situations. With knowledge only of the physiology of the adult as a guide, it is little wonder that reliable criteria of fetal distress are not readily available. The purpose of this paper is to set forth the character of fetal cardiovascular control and to provide a basis for the interpretation of it. With this new concept in mind, the problems of intrauterine fetal life and of neonatal adjustments after birth come more clearly into view. With the fetus in utero, attention focuses on the effects of the loss of gravitational pull on the body. The more fundamental question involved is the basic physiology of antigravity mechanisms upon the body. From this \;iewpoint, the entire spectrum of the consequences of weightIessness on the organism may be seen. Then evidence affirming the broad concept of sensory deprivation in general upon the body, and of antigrakrity deprivation in particular, may be looked for. In their book, Kybunetics of N&u,-al Systems,’ D. and K. Stanley-Jones establish a case for the concept that physiologic systems which are in a state of dynamic equilibrium-as are all living things---arc under the control of built-in mechanisms From the Dejmrt7uer1t of An,~tonz~. liniwrsity of Illinois College of Medicine. SuppoT-ted by United State.\ Public Nenlth Grant RG-4728.
which hold them under control. This is true “The of both homeostasis and posture. central nervous system is dependent for its the ceaseless influx of functioning upon neural permeability waves created by the activity of the sense organs.“l Without such an influx, the organism is in a state of sensory deprivation. In the case of the nervous system, mammals require that the spinal cord be connected with higher centers in order to exert a proper integration of muscle tone, for the spinal animal has flaccid muscles. The midbrain contains the principal central components which, under the stimulus of neural input from the periphery, can cause the opposite of flaccidity, \%z., rigidity. By neural integration of still higher centers the system acquires its normal tone with the potential for reflex voluntary or complex involuntary movements. The key to the system is sensory input from stretch receptors in all the striated muscles, the otoliths, and some from visual. auditory, and thermal sensory input. Fish differ from mammals. They lack the continuing sensory input from stretch receptors since they are supported by water against the pull of gravity. However, they arc (aquipped with lateral line organs which serve a comparable purpose in a different manner. Embryologically these organs are derived from the same rctodcrmal tissue as the \restibular apparatus of the inner car, whicll is concerned with postural or antigravity orientation in vertebrates. However, in fish. the system differs from that in mammals, for in fish a spinal animal is not flaccid; rather,
fetal
the spinal fish exhibits continuing and energetic movements. There is a runaway to a maximum of activity because the modulating influence of the lateral line refection (feedback) system working through the centers of the brain is lost. The key to control is continuing sensory input from specialized receptors lying in the lateral line modulating the reverberating neural circuits that keep the spinal fish active. In some invertebrates, similar feedbacks control the primitive neural system. StanleyJones points out that in the Medusa, Aurelia, there is a simple nerve net which has specialized receptors at eight points about the periphery of the umbrella-shaped organism. In each of these points is a small otolith-like structure which has the capacity to stimulate the nerve fibers with which they are associated. Movements of, or in, the water agitate these receptors from time to time. If these organs are removed one by one a Medusa will retain its upright and normal posture. However, after the last one is removed the Medusa collapses in a helpless heap. Sensory input normally keeps the simple nerve net in a state of continual excitation which permits the entire body to respond to other environmental stimuli where food or escape from danger is concerned. Again, the key to the problem is adequate sensory input keeping the neural net activated. Stanley-Jones makes an excellent case for regarding the role of sensory input from muscle spindles to be that of supplying the continual neural excitation (neural-dynamic) of the nervous system, including the brain, so that it can respond readily to the usual tactile, auditory, taste, visceral, and other stimuli. This bank of “neural dynamics must be replenished from time to time to maintain the nervous system in a reactive state.” There are two broad types of sense organs in the body, (a) those that exhibit rapid adaptation to a continuing stimulus and have a very brief or no afterdischarge and (b) those that adapt only very slowly to a continuing stimulus and which have very long after-discharge characteristics. The antigravity receptors of mammals, the otoliths,
adaptation
to
uterine
environment
801
and lateral lines of fish are of the second type. With these, there is assured a substantial and continuing input of nerve impulses into the nervous system in order to maintain the necessary reverberating neural activity of the brain. It is this, Stanley-Jones maintains, that provides the neurodynamic base upon which the normal responsiveness of an organism depends. Most of the work on weightlessness has been done in the field of aerospace medicine. It is concerned with the effects of weightlessness, achieved through water immersion as in a fetus in utero, on physical fitness, muscular strength, cardiovascular changes, metabolic and renal functions, psychomotor ability, respiratory activity, and the like, The decline of cardiovascular homeostasis has been most extensively studied in such a situation and some impairment of function shown as will be described below.2 It would be more instructive to approach the problem of weightlessness in another way. This would be to ascertain the characteristics of the circulation in individuals that have never had sensory input, or at least antigravity sensory input, and then to determine how soon a degree of homeostatic competence is achieved once antigravity sensory input is begun. This cannot be done easily in humans, but it has been done in fetal lambs, floating in utero, and in fetal lambs at cesarean section but with the placental circulation maintained. Embryologists until now have failed to consider the effect which a flotation type of existence has on the physiologic activity of the fetus, as opposed to the physiologic capability of the organism as it develops. In developmental biology it is axiomatic to say that morphologic differentiation of an organ or system precedes functional capability. This is equally true of a single organ system or of two or more interdependent systems such as homeostatic regulatory mechanisms. Less obvious is the fact, however, that full function of one or more completely developed secondary systems may not take place because a primary organ system essential to the secondary one is not yet called into action by the exigencies of the
802
Reynolds
environment. It is this sort of svstem-svstem interaction that concerns us here. An extensive literature exists in the field of fetal physiology. This is notably summarized by Windle3 and by Barcroft in their respective books on the subject. Nevertheless, it was not until 1954 when Dr. Paul, Dr. Huggett, and I” managed to record fetal blood pressure and heart rate of fetuses in utero, with the membranes intact, that the circulatory characteristics could be studied in a nearly normal environment. In such preparations, fetal responses to different stressful situations can be compared with those observed when the fetus is delivered by cesarean section and the piacental circulation maintained, as in conventional investigations of fetal physiology or with newborn lambs. Certain of the functional capabilities of the parasympathetic and sympathetic nervous systems have been explored, largely with the fetus in situ. The points of study were the responses of the fetal circulation to (a) change of intrauterine pressure”; (1~) graded degrees of hypoxia and nitrogen administration to, or asphyxia of, the ewe7 ; (c) disturbances of the maternal circulation8; (d) occlusion of the umbilical cord”; (e) vagotomylO; (f) stellate ganglionectomy of the fetus,lO and (g) excision of the fetal adrenal glands.1° The resting fetal heart rate decreases both when intrauterine pressure increases by a ,
Pig. 1. during Abolished fetus. A resulted permission
I
Periodic brddycardia of fetus (top line I uterine contraction (bottom line j by atropine injected directly into the slightly higher resting fetal heart rate (150 to 160 beats per minute). (Used by of Caldeyro-Barcia et al.‘*)
Fig. 2. Persistent vagotonia in a lamb fetus in utero following a strong stimulus. Top line, fetal umbilical arterial blood pressure (fetus in situ); fetal heart rate (circles). Next lint is not a physiologic event. Third line, carotid blood prrssure in ewe. Fourth line, respiratory activity in the ewe. Bottom line, 10 second intervals. At arrow, 1 ml. of 1 :lO,OOO epinephrine was injected into the umbilical vein of the fetus. Note fall in blood pressure and slower heart rate in the fetus. The heart rate of the fetus continued at 90 beats per minute.
weight placed upon the uterus and when the weight is removed. These are transient episodes evoked by a brief and dynamic stimulus. The bradycardia is vagal in origin since it is abolished by atropine. There is, therefore, a competent vagal mechanism which is brought into temporary action by this change in the environment. A lamb in utero and its mother respond differently to the same asphyxial stimulus. When nitrogen is given to a ewe, the heart rate and blood pressure rise. The fetus shows bradycardia and no change in blood pressure. When atropine is given to the fetus during bradycardia the heart rate becomes rapid. The bradycardia is vagally induced. Again we see that the autonomic system of the lamb responds to this stress by parasympathetic output and the fetal response is unlike that of the adult. Less stressful stimuli have an effect also. \Yhen a pregnant ewe is subjected to progressively stronger hypoxia, the fetal heart rate decreases, or it shows a 2: 1 heart block which is vagal in origin. Similarly, if there
Volume 83 Number
Fetal
6
are acute disturbances of the maternal circulation involving transient congestion of the maternal portion of the placenta, evanescent decreases in fetal heart rate occur. This is the result of induced vagotonia. From these and other experiments we conclude that the parasympathetic system of the fetal lamb in utero is functionally competent but it lacks a stimulus (sensory &put) to maintain parasympathetic tone. Most of the observations were made with the ewes lightly anesthetized with diallylethylbarbituric acid. It might be argued that this anesthetic abolishes existing vagal tone. This is unlikely, however, since vagotonia is the easiest response in the lamb to exhibit under this anesthesia. Procaine alone yields identical fetal responses to stress and the resting characteristics of the fetal circulation are the same. Barcroft described progressive vagotonia as a fetal lamb becomes larger. However, the in utero rates observed by him were
Table
I. Comparison
of the effect of carotid Blood
i Nonpregnant Lambs (6) Fetuses (5) “Per
Table
cent
ewe
( 10)
of
animals
showing
II. Comparison
III.
increase
‘Per
cent
0
I
ewes ( 12) (mean blood
occlusion
no
Blood
-
change
(O),
or
decrease
Heart
+
I
rate+
0
50 33 0
I
-
20 0 20
30 67 80
(-).
pressure
(mm.
Before
Hg)
Heart
After
101.5~8.9/81.8+8.2
rate
Before
87.3+8.5/64+6.6
(b.p.m.) I
After
110.4 + 8.5
99.5 2 6.5
70.5
234
194
37.8 k 2.4
166.7 2 13.7
158.8 k 14.0
blood
Comparison
of effects of hypoxia
(last trimester) animals
803
in fetuses, lambs, and ewes
37.924.4
of
I
0 0 20
85 (mean
environment
in fetuses, lambs, and ewes I
I
of the effects of vagotomy
I Ewes (15) Lambs (9) Fetuses (7)
artery
0 0 60 (+),
to uterine
recorded by auscultation and by palpation which involved some pressure upon and handling of the uterus which, as we have shown, induces vagotonia. From Barcroft’s experiments on lambs at cesarean section, it appears that the acute response to the stress of handling induces vagotonia, since he operated and observed very rapidly. He says, “Let me emphasize again, that if the phenomena which have just been described (fetal vagotonia) are to be observed they must be observed at once on the delivery of the fetus -a delivery which must be carried through with no strain on the uterine and umbilical blood vessels and no exposure of the cord or foetus-It may seem wasteful to do an experiment on a sheep which only takes ten minutes and produces but a single lesion, but it is less wasteful than for him to misinform himself on 3 or 4 matters.“4 Until very recently, there was no proof that the facts enumerated above established for the lamb bear a relation to the situation in
firessure*
I
100 100 20
(last trimester)
Nonpregnant Lambs (6) pressure) Fetuses (5) pressure)
Table
+
adaptation
showing
Blood 33.4 55.5 0 increase
in fetuses, lambs, and ewes firessure*
46.6 33.4 86.7 (+),
no
change
13.4 10.1 13.4 (O),
Heart
I
or
decrease
46 33.4 0 (-).
rate* 46.6 20.2 42.8
13.4 44.5 57.2
804
Reynolds
the human. In a recent report by CaldeyroBarcia and his associate? a brilliant experiment shows that a similarity exists. The fetal heart rate was recorded continuously and episodes of bradycardia (“dips” in the heart rate curve) were correlated directly with uterine contractions (Fig. 1) . Atropine was then injected directly into the leg of the fetus through the abdominal and uterine walls. The episodes of bradycardia were abolished, showing that they were vagotonic in origin. Moreover, the heart rate rose but slightly above the normal, preinjection level. The heart was, therefore virtually free of vagotonia unless sensory input from increased intrauterine pressure was active. Uterine contractions provide intermittent sensory input, which the sheep lacks, having an inactive uterus during gestation. If the heart has been stressed substantially, the heart rate (fetal lamb) remains below normal as vagotonia persists (Fig. 2). Caldeyro-Barcia and his associates have noticed this also with osytocin-induced excessive uterine activity. Concerning sympathetic activity in the fetus, evidence is meager but equally clear. When normal resting fetal heart rates in lambs are compared with resting heart rates after bilateral excision of the stellate and other thoracic sympathetic ganglia, no change occurs in resting fetal heart rate. This is true whether the vagi are intact or sectioned or both carotid sinus areas are excluded from the circulation. One must conclude that there is no appreciable resting sympathetic tone in the fetus so far as heart rate is concerned. One type of evidence has been obtained which demonstrated sympathetic system activity in the fetus. With the heart completely denervated, severe anoxia was produced by temporary occlusion of the umbilical cord. The heart rate showed a slow onset but profound decrease due to myocardial depression. On release of the cord, an extremely fast and prolonged tachycardia was seen. The fetus struggled, exhibited strong expiratory effort? and passed meconium. The experiment was repeated
after excision of both fetal adrenal glands. Now after anoxia, the heart rate returned to normal without the rebound tachycardia. In extremis, therefore, there was mass stimulation of the sympathetic system. One must conclude that the sympathetic system of the lamb fetus, like the parasympathetic system, is functionally competent but inactive in a resting fetus devoid of sensory input. One asks, therefore, why a developed and competent autonomic system is silent except in the face of transient and dynamic stresses. There is a similarity between these data in the lamb and results in humans reported by Caldeyro-Rarcia and his associates.ll They lind that after fairly severe abuse of the fetus by excessive uterine contractions, the heart rate rebounds in a runaway tachycardia of inany minutes’ duration. During prolonged excessive uterine activity, the heart rate remains below its normal level in a state of (‘adaptation,” sustained probably, but not yet demonstrated, by vagotonia. Rebound tachycardia then follows cessation of the excessive uterine activity: as the pendulum swings from a vagotonia to a sympathicotonia when the insult is withdrawn. Study of the development of cardiovascular responses in lambs soon after birth is crucial to the hypothesis suggested above. .4 few observations have been made in lambs from 4 to 12 days of age, averaging about 8 days. Responses to the following stresses have been studied: carotid artery occlusion (6 lambs) ; bilateral vagotomy (8 lambs) ; severe hypoxia (9 lambs). The results are summarized in Tables I, II, and III. Table I shows that carotid artery occlusion in lambs yields a rise in blood pressure as in the adult; the heart rate response is more or less intermediate between the adult and the fetus. Table 11 shows that vagotomy in adult ewes and lambs causes a fall in blood pressure and a decrease in heart rate while blood pressure in fetuses is unchanged, although the decrease in heart rate occurs. The effect of vagotomy in the lamb parallels more closely the change in the adult than it does the fetus.
Volume 83 Number6
Fetal
adaptation
to uterine
environment
R- 1034 APGAR 8
BIRTH
80 70 60 RESP. SO 40
805
30 1 2OOr
Stool 4
Vo,dmg J
HOURS
FETAL
Fig. 3. Term infant, 3,430 grams, born to a 34-year-old gravida viii, para v (one abortion, one ectopic pregnancy) white woman. Nonclinic patient. Labor, 2 hours, 50 minutes (precipitate). Pudendal block prior to delivery. No premeditation. The infant showed acceleration of heart rate after delivery. The fetal heart rate was 80 beats per minute 2 minutes prior to delivery and 110 beats per minute at one minute prior to delivery. During the first 3 hours, the infant showed marked activity with tremors and outcries. Pulsations of the umbilical cord were palpable between 15 minutes and 2 hours, 15 minutes. (Used by permission of M. M. Desmond, R. Franklin, M. Vallbona, and R. M. Hill: Unpublished data. 1
There is great variability of response in the effects of severe hypoxia in all three groups. Table III shows that the blood pressure of the fetus was, with one exception, unaffected by acute hypoxia. The responses in lambs and adults are rather similar. The heart rates are variable, but once again the lambs and ewes resemble each other to the extent that some of each showed cardiac acceleration which was not seen in the fetus. These data suggest that newborn lambs resemble adults more than fetuses in their responses to the three stresses employed. More refined experiments are needed to establish this point, but the evidence seems clear that circulatory
homeostasis
begins
soon
after
birth in the sheep. The question of how the changes in newborn lambs relate to the human newborn is not entirely a moot point. Desmond and her associates12 have carefully and critically evaluated the minute by minute changes in
the human from just before or just after birth to the tenth hour. They show (Fig. 3) that before birth there is progressive bradycardia as might be expected from the work of Caldeyro-Barcia and co-workers with the increasing work of labor. There is a rebound tachycardia within the first few minutes which only gradually subsides. After an initial sleep, when the heart rate holds reasonably constant at about 140 beats per minute, there is increased heart rate associated with gagging, coughing, and hiccups about the seventh to the tenth hour, when sensory disturbances are bothering the baby. In short, while much remains to be done, it is clear that the early responses resemble fetal behavior, but this gives way with time to a more or less stabilized situation that persists so long as the baby is quiet. Recent experiments on men given bed restI or immersed in water for a day to a week* show that cardiovascular homeostasis
806
March 15, lY62 Am. J. Obst. & Cynec.
Reynolds
depends upon proprioceptive input to the central nervous system. Following immersion there is a progressive decline in blood pressure: an increase in heart rate? and a loss of the diurnal variation in heart rate. The heart rate response to the mild stress of a tilt table is much exaggerated. An elevation of diastolic and a decrease of systolic blood pressure occurs, signifying diminishing cardiac output. With more severe stress of exercise on a treadmill, the deficiency of homeostasis is more evident as the response is more exaggerated. In short, prolonged reduction of proprioceptive input by weightlessness leads to loss of effective vagotonic regulation of the heart in man. The concept that homeostatic regulatory mechanisms depend upon sensory input to the nervous system is nicely set forth in the recent book by Stanley-Jones1 entitled The Kybernetics of Natural Systems, mentioned above, in which the roles of positive and negative feedbacks in a wide range of biologic systems are reviewed. Feedbacks stabilize physiologic mechanisms resulting in homeostasis; consequently, they prevent a runaway to a maximum (e.g., excessive sympathetic activity as in the crying baby, the distressed fetus, or the exercising deconditioned man) .” Gravity evokes sustained positive refection to skeletal muscle in order to maintain tonus and negative refect.ion (vagal tone) of the autonomic system in order to hold the cardiovascular system at a functional, stabilized level. It is this which the fetus lacks and the immersed man has lost. Speaking of weightless adults deprived of all sensory input, Stanley- Jones says, “The physical status of adults in these circumstances resembles nothing so much as a return to the foetal condition of isothermal floating in the amniotic fluid of the womb; it is not surprising therefore that the body regression to prenatal conditions should cause a similar regression on the mental plane.” With respect to the latter reference. thr reader shollld consult an editorial on the subject.” The fetus in utero, like the immersed man in the experiment of Graveline, is a freefloating organism. As in that experiment, the
fetus is in a sort of zero gravity situation so far as weight is concerned. It is not called upon to use its proprioceptive reflexes in order to offset the effect of gravity for the purpose of maintaining posture. The fetus is not normally subject to unequal forces until near term. It does possess from a time early in development the capacity for well-characterized patterns of behavioral (dynamic as opposed to postural) responses as Coghill’” and HookeP have shown, although Windle3 is of different opinion regarding their nature. After delivery in those species that are mature at birth antigravity input to the central nervous system is established rapidly. It appears, therefore? that such sensory input to the central nervous system is an essential factor in contributing to sustained parasympathetic system output, so far as cardio\.ascular homeostasis is concerned. This problem is part of the larger one of sensor) deprivation in general upon the body. How effective homeostasis will be after hirth must vary with the degree of morphologic maturity at birth. Opossums, hamsters. mice, rats, rabbits, kittens, puppies, piglets, human babies, and many other species will lack the capacity for sensitive homeostasis at a stabilized functional level at birth because they do not respond to gravity. Others, such as guinea pigs. foals: lambs: calves. kids, and many other species will possess to a marked degree the capacity for effective homeostasis since they can stand, walk (or run), and regulate body temperature fairly well when they are born. Most notably, they possess a capacity for proprioceptive input to the central nervous system when delivered from a condition of weightlessness during development. It is a captivating thought that the uterus is the original space capsule of mankind, and that all men have been, so to speak. in wei,ghtlrss orhit before the): were horn, Weightlessness
and
kybernetic
principles
We may now consider the weightless lamb fetus with the weightless man. Each is an organism which is deficient in certain regulatory mechanisms. The fetus is relatively lack-
Fetal
ing in both parasympathetic and sympathetic controls in the resting state. The circulation functions as does a heart-lung preparation, being under chemical control. The output side of the parasympathetic system (negative refection) may be evoked by a gentle, transient stimulus; that of the sympathetic system (positive refection) with stronger stimulation. A man immersed for a week loses efficient parasympathetic control, since his resting heart rate increases and with mild or severe stress his sympathetic activity (positive refection) is much exaggerated, as in neurasthenia and in the deconditioned state. Viewed against the principles of stabilizing and runaway refection as described by Stanley- Jones,l the above situations come into perspective. Stabilizing refection of the heart rate depends upon negative feedback. The input of refective neural energy is governed by the output of energy to maintain posture. “Any system in dynamic equilibrium which is steady in the sense of stationary, or oscillating about a fixed point at midway, is regarded as stable. It owes its stability to the pattern of its monitor feed-backs. . . , If therefore oscillation is taken to be a form of stability, or as evidence of stability (rather than instability) it is permissible to generalize that stability (including oscillation) invariably demands negative feed-back. . . . When monitored by a stabilizing system, however, and subject to controlled release, positive feed-back enables the output to rise briefly to heights far above the normal optimal or safety limit, but often at the expense of prodigious expenditure of fuel.“” The antigravity mechanisms provide negative (parasympathetic) feedback to maintain the normal dynamic cardiovascular state to prevent a positive (sympathetic) feedback required by exertion from running away to a maximum while the body maintains skeletal muscle tonus. In the immersed man experiments lasting from 6 hours to 7 days, the negative feedback gradually disappears while the capacity for positive feedback upon exertion persists. In the lamb fetus, positive feedback does not normally exist to a marked degree unless the efferent aspect of it is in-
adaptation
to uterine
environment
807
duced by severe hypoxia in extremis. Negative feedback does not exist because there is no input to the nervous system from muscle spindles or otoliths. However, vagal activity, the efferent component of the system, is called into action by less moderate hypoxia or gentle stimuli of short duration. The antigravity component involving sustained output of energy of a low order to the cardiovascular system is absent. Consequently, the efferent component of the feedback monitoring system is brought into play only transiently since the neural dynamic, as StanleyJones calls it, of the central nervous system is minor from short-lasting episodes of sensory input to the central nervous system. Another evidence of the dependence of energy output on sensory input in the lamb fetus may be mentioned in conclusion. I refer to the response to chemoreceptor stimulation.l? It is well known that fetuses and the apneic newborn do not respond to chemoreceptor excitation, despite the fact that chemoreceptor organs are excited and bombarding the brain over the ninth nerve with what are normally excitatory (positive refectory) stimuli. If, however, a fetus is given artificial respiration, chemoreceptor stimulation now excites inspiratory effort. The response is abolished by vagotomy. Similarly, when a fetus is made to swallow by pulling the tongue, this is followed by a strong expiratory effort. Chemoreceptor activity now excites exaggerated expiratory effort. Chemoreceptors, it should be noted, exhibit almost no after-discharge. In these characteristics we witness a phenomenon similar to that of the antigravity mechanism: an external or environmental force provides neural input to the central nervous system, rendering it sensitive to the positive refection of chemoreceptor stimulation. The difference is that antigravity mechanisms (muscle spindles) and their associated neuronal connections excite the stabilizing action of negative feedback to the heart; the chemoreceptor mechanism excites positive refection by reflex excitation of the muscles of respiration with the purpose of improving pulmonary ventilation for a few moments.
808
Reynolds
REFERENCES
Stanley-Jones, D. and I(.: The Kybernetics of Natural Systems, New York. 1960, Pergamon Press, Inc. 2. Graveline, D. E., Balke, B., McKenzie, R. E.; and Hartman, B.: Aerospace Med. 32: 387, 1961. 3. Windle, W. F.: Physiology of the Fetus, Philadelphia, 1940, W. B. Saunders Company. 4. Barcroft, J.: Researches in Pre-natal Lifr. 1947, Charles C Thomas, Springfield, Ill., Publisher. 5. Reynolds, S. R. M., Paul, W. M., and Huggett, A. St. G.: Bull. Johns Hopkins Hosp. 95: 256, 1954. 6. Reynolds, S. R. M., and Paul, W. M.: Bull. Johns Hopkins Hosp. 97: 3837, 1955. 7. Reynolds, S. R. M., and Paul, W. M.: .4m. J. Physiol. 193: 249, 1958. 8. Bieniarz, J., and Reynolds, S. R. M.: Am. J. Physiol. 198: 128, 1960. 9. Reynolds, S. R. M.: Am. J, Physiol. 176: 162, 1954.
IO.
I.
1 I.
12.
13. 14. 15.
16.
17.
Reynolds, 8. R. M.: .4m. J. Physiol. 176: 169, 1954. Caldeyro-Barcia, R., et al.: Efl‘ect of Uterine Contractions During Labor on the Human Fetus and Newborn. Fourth International Conference on Medical Electronics, New York, July 16-24, 1961. Desmond, M. M., Pap, L. F., Hill, R. M., and von Minden, M. C., Thirty-first Annual Meeting of the Society for Pediatric Research, Atlantic City, May 4-5, 1961. (Page 106 of Abstracts.) Taylor, I-I. L., Henschel, A., Brozek, J., and Keys, A.: J. Appl. Physiol. 2: 223, 1949. Editorial, Brit. M. J. 2: 1224, 1956. Coghill, G. E.: Anatomy and the Problem of Behaviour, New York, 1929, The Macmillan Company. Hooker, D.: The Pre-natal Origin of Behavior, Lawrence, Kan., 1952, University of Kansas Press. Reynolds, S. R. M., and Mackie, J. D.: Am. J. Physiol. 201: 239, 1961.
R.
Chicago,
M.
a problem of sensory deprivation
REYNOLDS,
PH.D.,
D.Sc.
Illinois
0 B S T E T R I c I A N s are concerned with fetal cardiovascular physiology whenever they listen to a fetal heart. The problem is to distinguish between “normal” and “distress” situations. With knowledge only of the physiology of the adult as a guide, it is little wonder that reliable criteria of fetal distress are not readily available. The purpose of this paper is to set forth the character of fetal cardiovascular control and to provide a basis for the interpretation of it. With this new concept in mind, the problems of intrauterine fetal life and of neonatal adjustments after birth come more clearly into view. With the fetus in utero, attention focuses on the effects of the loss of gravitational pull on the body. The more fundamental question involved is the basic physiology of antigravity mechanisms upon the body. From this \;iewpoint, the entire spectrum of the consequences of weightIessness on the organism may be seen. Then evidence affirming the broad concept of sensory deprivation in general upon the body, and of antigrakrity deprivation in particular, may be looked for. In their book, Kybunetics of N&u,-al Systems,’ D. and K. Stanley-Jones establish a case for the concept that physiologic systems which are in a state of dynamic equilibrium-as are all living things---arc under the control of built-in mechanisms From the Dejmrt7uer1t of An,~tonz~. liniwrsity of Illinois College of Medicine. SuppoT-ted by United State.\ Public Nenlth Grant RG-4728.
which hold them under control. This is true “The of both homeostasis and posture. central nervous system is dependent for its the ceaseless influx of functioning upon neural permeability waves created by the activity of the sense organs.“l Without such an influx, the organism is in a state of sensory deprivation. In the case of the nervous system, mammals require that the spinal cord be connected with higher centers in order to exert a proper integration of muscle tone, for the spinal animal has flaccid muscles. The midbrain contains the principal central components which, under the stimulus of neural input from the periphery, can cause the opposite of flaccidity, \%z., rigidity. By neural integration of still higher centers the system acquires its normal tone with the potential for reflex voluntary or complex involuntary movements. The key to the system is sensory input from stretch receptors in all the striated muscles, the otoliths, and some from visual. auditory, and thermal sensory input. Fish differ from mammals. They lack the continuing sensory input from stretch receptors since they are supported by water against the pull of gravity. However, they arc (aquipped with lateral line organs which serve a comparable purpose in a different manner. Embryologically these organs are derived from the same rctodcrmal tissue as the \restibular apparatus of the inner car, whicll is concerned with postural or antigravity orientation in vertebrates. However, in fish. the system differs from that in mammals, for in fish a spinal animal is not flaccid; rather,
fetal
the spinal fish exhibits continuing and energetic movements. There is a runaway to a maximum of activity because the modulating influence of the lateral line refection (feedback) system working through the centers of the brain is lost. The key to control is continuing sensory input from specialized receptors lying in the lateral line modulating the reverberating neural circuits that keep the spinal fish active. In some invertebrates, similar feedbacks control the primitive neural system. StanleyJones points out that in the Medusa, Aurelia, there is a simple nerve net which has specialized receptors at eight points about the periphery of the umbrella-shaped organism. In each of these points is a small otolith-like structure which has the capacity to stimulate the nerve fibers with which they are associated. Movements of, or in, the water agitate these receptors from time to time. If these organs are removed one by one a Medusa will retain its upright and normal posture. However, after the last one is removed the Medusa collapses in a helpless heap. Sensory input normally keeps the simple nerve net in a state of continual excitation which permits the entire body to respond to other environmental stimuli where food or escape from danger is concerned. Again, the key to the problem is adequate sensory input keeping the neural net activated. Stanley-Jones makes an excellent case for regarding the role of sensory input from muscle spindles to be that of supplying the continual neural excitation (neural-dynamic) of the nervous system, including the brain, so that it can respond readily to the usual tactile, auditory, taste, visceral, and other stimuli. This bank of “neural dynamics must be replenished from time to time to maintain the nervous system in a reactive state.” There are two broad types of sense organs in the body, (a) those that exhibit rapid adaptation to a continuing stimulus and have a very brief or no afterdischarge and (b) those that adapt only very slowly to a continuing stimulus and which have very long after-discharge characteristics. The antigravity receptors of mammals, the otoliths,
adaptation
to
uterine
environment
801
and lateral lines of fish are of the second type. With these, there is assured a substantial and continuing input of nerve impulses into the nervous system in order to maintain the necessary reverberating neural activity of the brain. It is this, Stanley-Jones maintains, that provides the neurodynamic base upon which the normal responsiveness of an organism depends. Most of the work on weightlessness has been done in the field of aerospace medicine. It is concerned with the effects of weightlessness, achieved through water immersion as in a fetus in utero, on physical fitness, muscular strength, cardiovascular changes, metabolic and renal functions, psychomotor ability, respiratory activity, and the like, The decline of cardiovascular homeostasis has been most extensively studied in such a situation and some impairment of function shown as will be described below.2 It would be more instructive to approach the problem of weightlessness in another way. This would be to ascertain the characteristics of the circulation in individuals that have never had sensory input, or at least antigravity sensory input, and then to determine how soon a degree of homeostatic competence is achieved once antigravity sensory input is begun. This cannot be done easily in humans, but it has been done in fetal lambs, floating in utero, and in fetal lambs at cesarean section but with the placental circulation maintained. Embryologists until now have failed to consider the effect which a flotation type of existence has on the physiologic activity of the fetus, as opposed to the physiologic capability of the organism as it develops. In developmental biology it is axiomatic to say that morphologic differentiation of an organ or system precedes functional capability. This is equally true of a single organ system or of two or more interdependent systems such as homeostatic regulatory mechanisms. Less obvious is the fact, however, that full function of one or more completely developed secondary systems may not take place because a primary organ system essential to the secondary one is not yet called into action by the exigencies of the
802
Reynolds
environment. It is this sort of svstem-svstem interaction that concerns us here. An extensive literature exists in the field of fetal physiology. This is notably summarized by Windle3 and by Barcroft in their respective books on the subject. Nevertheless, it was not until 1954 when Dr. Paul, Dr. Huggett, and I” managed to record fetal blood pressure and heart rate of fetuses in utero, with the membranes intact, that the circulatory characteristics could be studied in a nearly normal environment. In such preparations, fetal responses to different stressful situations can be compared with those observed when the fetus is delivered by cesarean section and the piacental circulation maintained, as in conventional investigations of fetal physiology or with newborn lambs. Certain of the functional capabilities of the parasympathetic and sympathetic nervous systems have been explored, largely with the fetus in situ. The points of study were the responses of the fetal circulation to (a) change of intrauterine pressure”; (1~) graded degrees of hypoxia and nitrogen administration to, or asphyxia of, the ewe7 ; (c) disturbances of the maternal circulation8; (d) occlusion of the umbilical cord”; (e) vagotomylO; (f) stellate ganglionectomy of the fetus,lO and (g) excision of the fetal adrenal glands.1° The resting fetal heart rate decreases both when intrauterine pressure increases by a ,
Pig. 1. during Abolished fetus. A resulted permission
I
Periodic brddycardia of fetus (top line I uterine contraction (bottom line j by atropine injected directly into the slightly higher resting fetal heart rate (150 to 160 beats per minute). (Used by of Caldeyro-Barcia et al.‘*)
Fig. 2. Persistent vagotonia in a lamb fetus in utero following a strong stimulus. Top line, fetal umbilical arterial blood pressure (fetus in situ); fetal heart rate (circles). Next lint is not a physiologic event. Third line, carotid blood prrssure in ewe. Fourth line, respiratory activity in the ewe. Bottom line, 10 second intervals. At arrow, 1 ml. of 1 :lO,OOO epinephrine was injected into the umbilical vein of the fetus. Note fall in blood pressure and slower heart rate in the fetus. The heart rate of the fetus continued at 90 beats per minute.
weight placed upon the uterus and when the weight is removed. These are transient episodes evoked by a brief and dynamic stimulus. The bradycardia is vagal in origin since it is abolished by atropine. There is, therefore, a competent vagal mechanism which is brought into temporary action by this change in the environment. A lamb in utero and its mother respond differently to the same asphyxial stimulus. When nitrogen is given to a ewe, the heart rate and blood pressure rise. The fetus shows bradycardia and no change in blood pressure. When atropine is given to the fetus during bradycardia the heart rate becomes rapid. The bradycardia is vagally induced. Again we see that the autonomic system of the lamb responds to this stress by parasympathetic output and the fetal response is unlike that of the adult. Less stressful stimuli have an effect also. \Yhen a pregnant ewe is subjected to progressively stronger hypoxia, the fetal heart rate decreases, or it shows a 2: 1 heart block which is vagal in origin. Similarly, if there
Volume 83 Number
Fetal
6
are acute disturbances of the maternal circulation involving transient congestion of the maternal portion of the placenta, evanescent decreases in fetal heart rate occur. This is the result of induced vagotonia. From these and other experiments we conclude that the parasympathetic system of the fetal lamb in utero is functionally competent but it lacks a stimulus (sensory &put) to maintain parasympathetic tone. Most of the observations were made with the ewes lightly anesthetized with diallylethylbarbituric acid. It might be argued that this anesthetic abolishes existing vagal tone. This is unlikely, however, since vagotonia is the easiest response in the lamb to exhibit under this anesthesia. Procaine alone yields identical fetal responses to stress and the resting characteristics of the fetal circulation are the same. Barcroft described progressive vagotonia as a fetal lamb becomes larger. However, the in utero rates observed by him were
Table
I. Comparison
of the effect of carotid Blood
i Nonpregnant Lambs (6) Fetuses (5) “Per
Table
cent
ewe
( 10)
of
animals
showing
II. Comparison
III.
increase
‘Per
cent
0
I
ewes ( 12) (mean blood
occlusion
no
Blood
-
change
(O),
or
decrease
Heart
+
I
rate+
0
50 33 0
I
-
20 0 20
30 67 80
(-).
pressure
(mm.
Before
Hg)
Heart
After
101.5~8.9/81.8+8.2
rate
Before
87.3+8.5/64+6.6
(b.p.m.) I
After
110.4 + 8.5
99.5 2 6.5
70.5
234
194
37.8 k 2.4
166.7 2 13.7
158.8 k 14.0
blood
Comparison
of effects of hypoxia
(last trimester) animals
803
in fetuses, lambs, and ewes
37.924.4
of
I
0 0 20
85 (mean
environment
in fetuses, lambs, and ewes I
I
of the effects of vagotomy
I Ewes (15) Lambs (9) Fetuses (7)
artery
0 0 60 (+),
to uterine
recorded by auscultation and by palpation which involved some pressure upon and handling of the uterus which, as we have shown, induces vagotonia. From Barcroft’s experiments on lambs at cesarean section, it appears that the acute response to the stress of handling induces vagotonia, since he operated and observed very rapidly. He says, “Let me emphasize again, that if the phenomena which have just been described (fetal vagotonia) are to be observed they must be observed at once on the delivery of the fetus -a delivery which must be carried through with no strain on the uterine and umbilical blood vessels and no exposure of the cord or foetus-It may seem wasteful to do an experiment on a sheep which only takes ten minutes and produces but a single lesion, but it is less wasteful than for him to misinform himself on 3 or 4 matters.“4 Until very recently, there was no proof that the facts enumerated above established for the lamb bear a relation to the situation in
firessure*
I
100 100 20
(last trimester)
Nonpregnant Lambs (6) pressure) Fetuses (5) pressure)
Table
+
adaptation
showing
Blood 33.4 55.5 0 increase
in fetuses, lambs, and ewes firessure*
46.6 33.4 86.7 (+),
no
change
13.4 10.1 13.4 (O),
Heart
I
or
decrease
46 33.4 0 (-).
rate* 46.6 20.2 42.8
13.4 44.5 57.2
804
Reynolds
the human. In a recent report by CaldeyroBarcia and his associate? a brilliant experiment shows that a similarity exists. The fetal heart rate was recorded continuously and episodes of bradycardia (“dips” in the heart rate curve) were correlated directly with uterine contractions (Fig. 1) . Atropine was then injected directly into the leg of the fetus through the abdominal and uterine walls. The episodes of bradycardia were abolished, showing that they were vagotonic in origin. Moreover, the heart rate rose but slightly above the normal, preinjection level. The heart was, therefore virtually free of vagotonia unless sensory input from increased intrauterine pressure was active. Uterine contractions provide intermittent sensory input, which the sheep lacks, having an inactive uterus during gestation. If the heart has been stressed substantially, the heart rate (fetal lamb) remains below normal as vagotonia persists (Fig. 2). Caldeyro-Barcia and his associates have noticed this also with osytocin-induced excessive uterine activity. Concerning sympathetic activity in the fetus, evidence is meager but equally clear. When normal resting fetal heart rates in lambs are compared with resting heart rates after bilateral excision of the stellate and other thoracic sympathetic ganglia, no change occurs in resting fetal heart rate. This is true whether the vagi are intact or sectioned or both carotid sinus areas are excluded from the circulation. One must conclude that there is no appreciable resting sympathetic tone in the fetus so far as heart rate is concerned. One type of evidence has been obtained which demonstrated sympathetic system activity in the fetus. With the heart completely denervated, severe anoxia was produced by temporary occlusion of the umbilical cord. The heart rate showed a slow onset but profound decrease due to myocardial depression. On release of the cord, an extremely fast and prolonged tachycardia was seen. The fetus struggled, exhibited strong expiratory effort? and passed meconium. The experiment was repeated
after excision of both fetal adrenal glands. Now after anoxia, the heart rate returned to normal without the rebound tachycardia. In extremis, therefore, there was mass stimulation of the sympathetic system. One must conclude that the sympathetic system of the lamb fetus, like the parasympathetic system, is functionally competent but inactive in a resting fetus devoid of sensory input. One asks, therefore, why a developed and competent autonomic system is silent except in the face of transient and dynamic stresses. There is a similarity between these data in the lamb and results in humans reported by Caldeyro-Rarcia and his associates.ll They lind that after fairly severe abuse of the fetus by excessive uterine contractions, the heart rate rebounds in a runaway tachycardia of inany minutes’ duration. During prolonged excessive uterine activity, the heart rate remains below its normal level in a state of (‘adaptation,” sustained probably, but not yet demonstrated, by vagotonia. Rebound tachycardia then follows cessation of the excessive uterine activity: as the pendulum swings from a vagotonia to a sympathicotonia when the insult is withdrawn. Study of the development of cardiovascular responses in lambs soon after birth is crucial to the hypothesis suggested above. .4 few observations have been made in lambs from 4 to 12 days of age, averaging about 8 days. Responses to the following stresses have been studied: carotid artery occlusion (6 lambs) ; bilateral vagotomy (8 lambs) ; severe hypoxia (9 lambs). The results are summarized in Tables I, II, and III. Table I shows that carotid artery occlusion in lambs yields a rise in blood pressure as in the adult; the heart rate response is more or less intermediate between the adult and the fetus. Table 11 shows that vagotomy in adult ewes and lambs causes a fall in blood pressure and a decrease in heart rate while blood pressure in fetuses is unchanged, although the decrease in heart rate occurs. The effect of vagotomy in the lamb parallels more closely the change in the adult than it does the fetus.
Volume 83 Number6
Fetal
adaptation
to uterine
environment
R- 1034 APGAR 8
BIRTH
80 70 60 RESP. SO 40
805
30 1 2OOr
Stool 4
Vo,dmg J
HOURS
FETAL
Fig. 3. Term infant, 3,430 grams, born to a 34-year-old gravida viii, para v (one abortion, one ectopic pregnancy) white woman. Nonclinic patient. Labor, 2 hours, 50 minutes (precipitate). Pudendal block prior to delivery. No premeditation. The infant showed acceleration of heart rate after delivery. The fetal heart rate was 80 beats per minute 2 minutes prior to delivery and 110 beats per minute at one minute prior to delivery. During the first 3 hours, the infant showed marked activity with tremors and outcries. Pulsations of the umbilical cord were palpable between 15 minutes and 2 hours, 15 minutes. (Used by permission of M. M. Desmond, R. Franklin, M. Vallbona, and R. M. Hill: Unpublished data. 1
There is great variability of response in the effects of severe hypoxia in all three groups. Table III shows that the blood pressure of the fetus was, with one exception, unaffected by acute hypoxia. The responses in lambs and adults are rather similar. The heart rates are variable, but once again the lambs and ewes resemble each other to the extent that some of each showed cardiac acceleration which was not seen in the fetus. These data suggest that newborn lambs resemble adults more than fetuses in their responses to the three stresses employed. More refined experiments are needed to establish this point, but the evidence seems clear that circulatory
homeostasis
begins
soon
after
birth in the sheep. The question of how the changes in newborn lambs relate to the human newborn is not entirely a moot point. Desmond and her associates12 have carefully and critically evaluated the minute by minute changes in
the human from just before or just after birth to the tenth hour. They show (Fig. 3) that before birth there is progressive bradycardia as might be expected from the work of Caldeyro-Barcia and co-workers with the increasing work of labor. There is a rebound tachycardia within the first few minutes which only gradually subsides. After an initial sleep, when the heart rate holds reasonably constant at about 140 beats per minute, there is increased heart rate associated with gagging, coughing, and hiccups about the seventh to the tenth hour, when sensory disturbances are bothering the baby. In short, while much remains to be done, it is clear that the early responses resemble fetal behavior, but this gives way with time to a more or less stabilized situation that persists so long as the baby is quiet. Recent experiments on men given bed restI or immersed in water for a day to a week* show that cardiovascular homeostasis
806
March 15, lY62 Am. J. Obst. & Cynec.
Reynolds
depends upon proprioceptive input to the central nervous system. Following immersion there is a progressive decline in blood pressure: an increase in heart rate? and a loss of the diurnal variation in heart rate. The heart rate response to the mild stress of a tilt table is much exaggerated. An elevation of diastolic and a decrease of systolic blood pressure occurs, signifying diminishing cardiac output. With more severe stress of exercise on a treadmill, the deficiency of homeostasis is more evident as the response is more exaggerated. In short, prolonged reduction of proprioceptive input by weightlessness leads to loss of effective vagotonic regulation of the heart in man. The concept that homeostatic regulatory mechanisms depend upon sensory input to the nervous system is nicely set forth in the recent book by Stanley-Jones1 entitled The Kybernetics of Natural Systems, mentioned above, in which the roles of positive and negative feedbacks in a wide range of biologic systems are reviewed. Feedbacks stabilize physiologic mechanisms resulting in homeostasis; consequently, they prevent a runaway to a maximum (e.g., excessive sympathetic activity as in the crying baby, the distressed fetus, or the exercising deconditioned man) .” Gravity evokes sustained positive refection to skeletal muscle in order to maintain tonus and negative refect.ion (vagal tone) of the autonomic system in order to hold the cardiovascular system at a functional, stabilized level. It is this which the fetus lacks and the immersed man has lost. Speaking of weightless adults deprived of all sensory input, Stanley- Jones says, “The physical status of adults in these circumstances resembles nothing so much as a return to the foetal condition of isothermal floating in the amniotic fluid of the womb; it is not surprising therefore that the body regression to prenatal conditions should cause a similar regression on the mental plane.” With respect to the latter reference. thr reader shollld consult an editorial on the subject.” The fetus in utero, like the immersed man in the experiment of Graveline, is a freefloating organism. As in that experiment, the
fetus is in a sort of zero gravity situation so far as weight is concerned. It is not called upon to use its proprioceptive reflexes in order to offset the effect of gravity for the purpose of maintaining posture. The fetus is not normally subject to unequal forces until near term. It does possess from a time early in development the capacity for well-characterized patterns of behavioral (dynamic as opposed to postural) responses as Coghill’” and HookeP have shown, although Windle3 is of different opinion regarding their nature. After delivery in those species that are mature at birth antigravity input to the central nervous system is established rapidly. It appears, therefore? that such sensory input to the central nervous system is an essential factor in contributing to sustained parasympathetic system output, so far as cardio\.ascular homeostasis is concerned. This problem is part of the larger one of sensor) deprivation in general upon the body. How effective homeostasis will be after hirth must vary with the degree of morphologic maturity at birth. Opossums, hamsters. mice, rats, rabbits, kittens, puppies, piglets, human babies, and many other species will lack the capacity for sensitive homeostasis at a stabilized functional level at birth because they do not respond to gravity. Others, such as guinea pigs. foals: lambs: calves. kids, and many other species will possess to a marked degree the capacity for effective homeostasis since they can stand, walk (or run), and regulate body temperature fairly well when they are born. Most notably, they possess a capacity for proprioceptive input to the central nervous system when delivered from a condition of weightlessness during development. It is a captivating thought that the uterus is the original space capsule of mankind, and that all men have been, so to speak. in wei,ghtlrss orhit before the): were horn, Weightlessness
and
kybernetic
principles
We may now consider the weightless lamb fetus with the weightless man. Each is an organism which is deficient in certain regulatory mechanisms. The fetus is relatively lack-
Fetal
ing in both parasympathetic and sympathetic controls in the resting state. The circulation functions as does a heart-lung preparation, being under chemical control. The output side of the parasympathetic system (negative refection) may be evoked by a gentle, transient stimulus; that of the sympathetic system (positive refection) with stronger stimulation. A man immersed for a week loses efficient parasympathetic control, since his resting heart rate increases and with mild or severe stress his sympathetic activity (positive refection) is much exaggerated, as in neurasthenia and in the deconditioned state. Viewed against the principles of stabilizing and runaway refection as described by Stanley- Jones,l the above situations come into perspective. Stabilizing refection of the heart rate depends upon negative feedback. The input of refective neural energy is governed by the output of energy to maintain posture. “Any system in dynamic equilibrium which is steady in the sense of stationary, or oscillating about a fixed point at midway, is regarded as stable. It owes its stability to the pattern of its monitor feed-backs. . . , If therefore oscillation is taken to be a form of stability, or as evidence of stability (rather than instability) it is permissible to generalize that stability (including oscillation) invariably demands negative feed-back. . . . When monitored by a stabilizing system, however, and subject to controlled release, positive feed-back enables the output to rise briefly to heights far above the normal optimal or safety limit, but often at the expense of prodigious expenditure of fuel.“” The antigravity mechanisms provide negative (parasympathetic) feedback to maintain the normal dynamic cardiovascular state to prevent a positive (sympathetic) feedback required by exertion from running away to a maximum while the body maintains skeletal muscle tonus. In the immersed man experiments lasting from 6 hours to 7 days, the negative feedback gradually disappears while the capacity for positive feedback upon exertion persists. In the lamb fetus, positive feedback does not normally exist to a marked degree unless the efferent aspect of it is in-
adaptation
to uterine
environment
807
duced by severe hypoxia in extremis. Negative feedback does not exist because there is no input to the nervous system from muscle spindles or otoliths. However, vagal activity, the efferent component of the system, is called into action by less moderate hypoxia or gentle stimuli of short duration. The antigravity component involving sustained output of energy of a low order to the cardiovascular system is absent. Consequently, the efferent component of the feedback monitoring system is brought into play only transiently since the neural dynamic, as StanleyJones calls it, of the central nervous system is minor from short-lasting episodes of sensory input to the central nervous system. Another evidence of the dependence of energy output on sensory input in the lamb fetus may be mentioned in conclusion. I refer to the response to chemoreceptor stimulation.l? It is well known that fetuses and the apneic newborn do not respond to chemoreceptor excitation, despite the fact that chemoreceptor organs are excited and bombarding the brain over the ninth nerve with what are normally excitatory (positive refectory) stimuli. If, however, a fetus is given artificial respiration, chemoreceptor stimulation now excites inspiratory effort. The response is abolished by vagotomy. Similarly, when a fetus is made to swallow by pulling the tongue, this is followed by a strong expiratory effort. Chemoreceptor activity now excites exaggerated expiratory effort. Chemoreceptors, it should be noted, exhibit almost no after-discharge. In these characteristics we witness a phenomenon similar to that of the antigravity mechanism: an external or environmental force provides neural input to the central nervous system, rendering it sensitive to the positive refection of chemoreceptor stimulation. The difference is that antigravity mechanisms (muscle spindles) and their associated neuronal connections excite the stabilizing action of negative feedback to the heart; the chemoreceptor mechanism excites positive refection by reflex excitation of the muscles of respiration with the purpose of improving pulmonary ventilation for a few moments.
808
Reynolds
REFERENCES
Stanley-Jones, D. and I(.: The Kybernetics of Natural Systems, New York. 1960, Pergamon Press, Inc. 2. Graveline, D. E., Balke, B., McKenzie, R. E.; and Hartman, B.: Aerospace Med. 32: 387, 1961. 3. Windle, W. F.: Physiology of the Fetus, Philadelphia, 1940, W. B. Saunders Company. 4. Barcroft, J.: Researches in Pre-natal Lifr. 1947, Charles C Thomas, Springfield, Ill., Publisher. 5. Reynolds, S. R. M., Paul, W. M., and Huggett, A. St. G.: Bull. Johns Hopkins Hosp. 95: 256, 1954. 6. Reynolds, S. R. M., and Paul, W. M.: Bull. Johns Hopkins Hosp. 97: 3837, 1955. 7. Reynolds, S. R. M., and Paul, W. M.: .4m. J. Physiol. 193: 249, 1958. 8. Bieniarz, J., and Reynolds, S. R. M.: Am. J. Physiol. 198: 128, 1960. 9. Reynolds, S. R. M.: Am. J, Physiol. 176: 162, 1954.
IO.
I.
1 I.
12.
13. 14. 15.
16.
17.
Reynolds, 8. R. M.: .4m. J. Physiol. 176: 169, 1954. Caldeyro-Barcia, R., et al.: Efl‘ect of Uterine Contractions During Labor on the Human Fetus and Newborn. Fourth International Conference on Medical Electronics, New York, July 16-24, 1961. Desmond, M. M., Pap, L. F., Hill, R. M., and von Minden, M. C., Thirty-first Annual Meeting of the Society for Pediatric Research, Atlantic City, May 4-5, 1961. (Page 106 of Abstracts.) Taylor, I-I. L., Henschel, A., Brozek, J., and Keys, A.: J. Appl. Physiol. 2: 223, 1949. Editorial, Brit. M. J. 2: 1224, 1956. Coghill, G. E.: Anatomy and the Problem of Behaviour, New York, 1929, The Macmillan Company. Hooker, D.: The Pre-natal Origin of Behavior, Lawrence, Kan., 1952, University of Kansas Press. Reynolds, S. R. M., and Mackie, J. D.: Am. J. Physiol. 201: 239, 1961.